Morales Ariadna E, Dong Yue, Brown Thomas, Baid Kaushal, Kontopoulos Dimitrios -Georgios, Gonzalez Victoria, Huang Zixia, Ahmed Alexis-Walid, Bhuinya Arkadeb, Hilgers Leon, Winkler Sylke, Hughes Graham, Li Xiaomeng, Lu Ping, Yang Yixin, Kirilenko Bogdan M, Devanna Paolo, Lama Tanya M, Nissan Yomiran, Pippel Martin, Dávalos Liliana M, Vernes Sonja C, Puechmaille Sebastien J, Rossiter Stephen J, Yovel Yossi, Prescott Joseph B, Kurth Andreas, Ray David A, Lim Burton K, Myers Eugene, Teeling Emma C, Banerjee Arinjay, Irving Aaron T, Hiller Michael
LOEWE Centre for Translational Biodiversity Genomics, Frankfurt, Germany.
Senckenberg Research Institute, Frankfurt, Germany.
Nature. 2025 Feb;638(8050):449-458. doi: 10.1038/s41586-024-08471-0. Epub 2025 Jan 29.
Zoonoses are infectious diseases transmitted from animals to humans. Bats have been suggested to harbour more zoonotic viruses than any other mammalian order. Infections in bats are largely asymptomatic, indicating limited tissue-damaging inflammation and immunopathology. To investigate the genomic basis of disease resistance, the Bat1K project generated reference-quality genomes of ten bat species, including potential viral reservoirs. Here we describe a systematic analysis covering 115 mammalian genomes that revealed that signatures of selection in immune genes are more prevalent in bats than in other mammalian orders. We found an excess of immune gene adaptations in the ancestral chiropteran branch and in many descending bat lineages, highlighting viral entry and detection factors, and regulators of antiviral and inflammatory responses. ISG15, which is an antiviral gene contributing to hyperinflammation during COVID-19 (refs. ), exhibits key residue changes in rhinolophid and hipposiderid bats. Cellular infection experiments show species-specific antiviral differences and an essential role of protein conjugation in antiviral function of bat ISG15, separate from its role in secretion and inflammation in humans. Furthermore, in contrast to humans, ISG15 in most rhinolophid and hipposiderid bats has strong anti-SARS-CoV-2 activity. Our work reveals molecular mechanisms that contribute to viral tolerance and disease resistance in bats.
人畜共患病是指从动物传播给人类的传染病。有研究表明，蝙蝠携带的人畜共患病毒比其他任何哺乳动物目都多。蝙蝠感染病毒后大多没有症状，这表明其组织损伤性炎症和免疫病理学反应有限。为了研究抗病性的基因组基础，Bat1K项目绘制了包括潜在病毒宿主在内的10种蝙蝠的参考质量基因组。在此，我们描述了一项涵盖115个哺乳动物基因组的系统分析，结果显示，与其他哺乳动物目相比，蝙蝠免疫基因中的选择特征更为普遍。我们发现，在蝙蝠祖先分支和许多衍生的蝙蝠谱系中，免疫基因适应性过剩，其中突出的是病毒进入和检测因子，以及抗病毒和炎症反应的调节因子。ISG15是一种抗病毒基因，在COVID-19期间会导致过度炎症反应，在菊头蝠和蹄蝠中，该基因的关键残基发生了变化。细胞感染实验表明，蝙蝠ISG15在抗病毒功能上存在物种特异性差异，且蛋白质结合在其中起着至关重要的作用，这与其在人类分泌和炎症中的作用不同。此外，与人类不同，大多数菊头蝠和蹄蝠中的ISG15具有很强的抗SARS-CoV-2活性。我们的研究揭示了蝙蝠对病毒耐受和抗病的分子机制。
